Neural Control of Choroidal Function

脉络膜功能的神经控制

• 批准号: 10716937
• 负责人: Paul Douglas Gamlin
• 金额: $ 54.57万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716937
• 关键词: Address; Affect; Age related macular degeneration; Anatomy; Angiography; Autonomic Pathways; Autopsy; Birds; Blood Pressure; Blood capillaries; Blood flow; Bruch' s basal membrane structure; Cell Nucleus; Chemicals; Choroid; Compensation; Darkness; Diabetic Retinopathy; Disease; Electrophysiology (science); Electroretinography; Eye; Eye diseases; Future; Ganglia; Goals; Health; Histology; Hour; Human; Injections; Insulin-Dependent Diabetes Mellitus; Investigation; Label; Laser-Doppler Flowmetry; Lasers; Lesion; Life; Light; Lighting; Location; Long-Term Effects; Macular degeneration; Magnetic Resonance Imaging; Measures; Mediating; Metabolic; Modeling; Motor; Motor Neurons; Neuroanatomy; Neurons; Nucleus solitarius; Optical Coherence Tomography; Parasympathetic Nervous System; Pathway interactions; Perfusion; Photic Stimulation; Photoreceptors; Physiology; Primates; Rabies; Rabies virus; Reporting; Rest; Retina; Retinal Ganglion Cells; Rodent; Role; Serous; Structure of ciliary ganglion; Structure of retinal pigment epithelium; Synapses; Thick; Time; Tracer; Vascular blood supply; Vertebrate Photoreceptors; Vision; Visual Fields; circadian; electrical microstimulation; experimental study; fovea centralis; improved; inflammatory marker; intravitreal injection; luminance; macula; melanopsin; nerve supply; neural; neural circuit; neuroregulation; nonhuman primate; paraventricular nucleus; pharmacologic; response; suprachiasmatic nucleus; visual stimulus

PROJECT SUMMARY In primates, including humans, the macula and especially the fovea, is critical for high-acuity vision. The metabolic needs of the fovea and macula are primarily met by the choriocapillaris, the capillary network of the choroid located immediately behind Bruch’s membrane. There is considerable evidence that compromised choroidal perfusion contributes to many eye diseases, such as age-related macular degeneration and diabetic retinopathy, that affect these retinal regions. Importantly, choroidal blood flow is substantially controlled by inputs from the parasympathetic nervous system. However, the parasympathetic circuitry controlling the choroidal vasculature in primates is very poorly understood. The precise locations of the pre- and postganglionic parasympathetic motoneurons supplying the choroid, as well as their premotor inputs have not been established, nor have the functional roles of these neurons been fully defined. Therefore, the overall goal of this proposal is to determine the location and function of the parasympathetic circuits controlling the choroidal vasculature in non-human primates. We propose to perform neuroanatomical, electrophysiological, and pharmacological experiments to address these questions. Specifically, in Aim 1, we will use retrograde tracers, both conventional and trans-synaptic, to identify the motor and premotor circuitry controlling the parasympathetic innervation of the choroid. In the functional part of the study, we will use infrared (IR) laser doppler flowmetry, IR laser speckle flowgraphy (LSFG), and optical coherence tomography (OCT)/OCT angiography (OCTA) to measure the choroidal vasculature. Specifically, in Aim 2, we will study the effects on the choroidal vasculature of modulating preganglionic motoneuron activity by electrical microstimulation and of modulating retinal activity by light. In Aim 3A, we hypothesize that pharmacological inactivation of preganglionic motoneurons reduces overall choroidal blood flow and thickness in darkness, reduces choroidal blood flow compensation for changes in blood pressure, and eliminates luminance induced changes in the choroidal vasculature. In Aim 3B, we hypothesize that electrolytic or chemical lesions of preganglionic motoneurons will result in reduced choroidal blood flow. In the long term, we hypothesize that the retina will show evidence of outer segment loss and inflammatory markers. We will non-invasively assess retina, retinal pigment epithelium, and choroid health in life by OCT/OCTA, LSFG, and electroretinogram (ERG)/multifocal ERG. We will further assess retinal health postmortem by retinal histology. The proposed experiments will constitute the first extensive and systematic investigation of the circuitry and role of the parasympathetic, preganglionic neurons controlling blood flow in the choroidal vasculature of a primate. These results will set the stage for future studies in which this circuitry is modulated in order to improve the survival of central vision in human macular degeneration.

项目概要 在包括人类在内的灵长类动物中，黄斑，尤其是中央凹，对于高敏锐度视力至关重要。这 中央凹和黄斑的代谢需求主要由脉络膜毛细血管满足，脉络膜毛细血管是视网膜的毛细血管网络。 脉络膜位于布鲁赫膜的正后方。有相当多的证据表明 脉络膜灌注会导致许多眼部疾病，例如年龄相关性黄斑变性和糖尿病 视网膜病变，影响这些视网膜区域。重要的是，脉络膜血流基本上由以下因素控制： 来自副交感神经系统的输入。然而，副交感神经回路控制 人们对灵长类动物的脉络膜血管系统知之甚少。预置和预置的精确位置 供应脉络膜的节后副交感运动神经元及其前运动输入没有 尚未确定，这些神经元的功能作用也尚未完全确定。因此，总体目标 该提案的目的是确定控制副交感神经回路的位置和功能 非人类灵长类动物的脉络膜脉管系统。我们建议进行神经解剖学、电生理学、 和药理学实验来解决这些问题。具体来说，在目标 1 中，我们将使用逆行 传统的和跨突触的示踪剂，用于识别控制运动的运动和前运动电路 脉络膜的副交感神经支配。在研究的功能部分，我们将使用红外（IR）激光 多普勒血流测定、红外激光散斑血流成像 (LSFG) 和光学相干断层扫描 (OCT)/OCT 血管造影（OCTA）来测量脉络膜血管系统。具体来说，在目标 2 中，我们将研究对 通过电微刺激调节节前运动神经元活动的脉络膜脉管系统 通过光调节视网膜活动。在目标 3A 中，我们假设药物失活 节前运动神经元减少黑暗中脉络膜的整体血流量和厚度，减少脉络膜 血流补偿血压的变化，并消除亮度引起的变化 脉络膜血管系统。在目标 3B 中，我们假设节前的电解或化学损伤 运动神经元会导致脉络膜血流量减少。从长远来看，我们假设视网膜将 显示外节丢失和炎症标记物的证据。我们将非侵入性地评估视网膜、视网膜 通过 OCT/OCTA、LSFG 和视网膜电图 (ERG)/多焦点检查生活中的色素上皮和脉络膜健康 尔格。我们将通过视网膜组织学进一步评估死后视网膜健康状况。拟议的实验将 构成了对副交感神经回路和作用的首次广泛而系统的研究， 控制灵长类动物脉络膜脉管系统血流的节前神经元。这些结果将设定 未来研究的阶段，其中该电路被调制以提高中央视觉的存活率 人类黄斑变性。